title: Sedative drug modulates T-cell and lymphocyte function-associated antigen-1 function.
abstract: BACKGROUND
  Sedative drugs modify immune cell functions via several mechanisms. However, the effects of sedatives on immune function have been primarily investigated in neutrophils and macrophages, and to the lesser extent lymphocytes. Lymphocyte function-associated antigen-1 (LFA-1) is an adhesion molecule that has a central role in regulating immune function of lymphocytes including interleukin-2 (IL-2) production and lymphocyte proliferation. Previous clinical studies reported that propofol and isoflurane reduced IL-2 level in patients, but midazolam did not. We previously demonstrated that isoflurane inhibited LFA-1 binding to its counter ligand, intercellular adhesion molecule-1 (ICAM-1), which might contribute to the reduction of IL-2 levels. In the current study, we examined the effect of propofol, midazolam, and dexmedetomidine on LFA-1/ICAM-1 binding, and the subsequent biological effects.
  
  
  METHODS
  The effect of sedative drugs on T-cell proliferation and IL-2 production was measured by calorimetric assays on human peripheral blood mononuclear cells. Because LFA-1/ICAM-1 binding has an important role in T-cell proliferation and IL-2 production, we measured the effect of sedative drugs on ICAM-1 binding to LFA-1 protein (cell-free assay). This analysis was followed by flow cytometric analysis of LFA-1 expressing T-cell binding to ICAM-1 (cell-based assay). To determine whether the drug/LFA-1 interaction is caused by competitive or allosteric inhibition, we analyzed the sedative drug effect on wild-type and high-affinity LFA-1 and a panel of monoclonal antibodies that bind to different regions of LFA-1.
  
  
  RESULTS
  Propofol at 10 to 100 μM inhibited ICAM-1 binding to LFA-1 in cell-free assays and cell-based assays (P < 0.05). However, dexmedetomidine and midazolam did not affect LFA-1/ICAM-1 binding. Propofol directly inhibits LFA-1 binding to ICAM-1 by binding near the ICAM-1 contact area in a competitive manner. At clinically relevant concentrations, propofol, but not dexmedetomidine or midazolam, inhibited IL-2 production (P < 0.05). Additionally, propofol inhibited lymphocyte proliferation (P < 0.05).
  
  
  CONCLUSIONS
  Our study suggests that propofol competitively inhibits LFA-1 binding to ICAM-1 on T-cells and suppresses T-cell proliferation and IL-2 production, whereas dexmedetomidine and midazolam do not significantly influence these immunological assays.
authors.affiliation: Department of Anesthesiology, Pain and Perioperative Medicine, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115, USA. koichi.yuki@childrens.harvard.edu
authors.forename: Koichi
authors.initials: K
authors.lastname: Yuki
authors.forename: Sulpicio G
authors.initials: SG
authors.lastname: Soriano
authors.forename: Motomu
authors.initials: M
authors.lastname: Shimaoka
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006993:Hypnotics and Sedatives / Q000378:metabolism / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology*
chemical_list: D006993:Hypnotics and Sedatives; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1